Massage Therapy for Osteoarthritis of the Knee: A

Randomized Dose-Finding Trial

Adam I. Perlman1*, Ather Ali2, Valentine Yanchou Njike2, David Hom3,4, Anna Davidi2, Susan Gould-
Fogerite4, Carl Milak4, David L. Katz2
1 Duke Integrative Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America, 2 Prevention Research Center, Yale University School
of Medicine, Derby, Connecticut, United States of America, 3 Clinical Trials Unit, Section of Infectious Diseases, Boston Medical Center, Boston, Massachusetts, United
States of America, 4 School of Health Related Professions, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America

Abstract
Background: In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and
possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination.

Methods: We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further
examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week
regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control.
Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range
of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks.

Results: WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute
massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC
subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in
the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no
significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on
WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week
dose.

Conclusion: Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-
world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future
trials.

Trial Registration: ClinicalTrials.gov NCT00970008

Citation: Perlman AI, Ali A, Njike VY, Hom D, Davidi A, et al. (2012) Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial. PLoS
ONE 7(2): e30248. doi:10.1371/journal.pone.0030248
Editor: Ulrich Thiem, Marienhospital Herne - University of Bochum, Germany
Received July 25, 2011; Accepted December 14, 2011; Published February 8, 2012
Copyright: ß 2012 Perlman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This publication was made possible by grant number R01 AT004623 from the National Center for Complementary and Alternative Medicine (NCCAM)
at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCCAM. The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: adam.perlman@duke.edu

Introduction cardiac toxicity, as well as the removal of additional COX-2

Osteoarthritis (OA) is a slowly progressive degenerative disease
of the joints that at present afflicts approximately 27 million
Americans [1,2]. With the aging of the ‘‘baby boom’’ population
and increasing rates of obesity, the prevalence of OA is estimated
to increase 40% by 2025 [3]. Conventional therapies for OA have
limited effectiveness, and toxicities associated with suitable drugs
thus often limit utilization, leaving many facing surgery or chronic,
often debilitating, pain, muscle weakness, lack of stamina, and loss
of function [3,4,5,6,7,8,9,10]. In 2005, US costs from OA related
absenteeism alone were estimated at $10.3 billion, and in 2007,
OA increased aggregate annual medical care expenditures by
$185.5 billion (in 2007 dollars) [11]. Well-publicized events such as
the multiple lawsuits associated with rofecoxib and potential
inhibitors from the market, have lessened the public’s confidence
in pharmaceuticals and led to increased interest in therapeutic
interventions believed to be safer [12,13,14].
Massage therapy and certain other complementary and
alternative medicine (CAM) interventions are being utilized by
OA sufferers, and represent attractive, potentially effective options
to manage pain [12,13,14,15,16,17,18]. Massage is one of the
most popular CAM therapies in the US [14]. Between 2002 and
2007, the 1-year prevalence of use of massage by the US adult
population increased from 5% (10.05 million) to 8.3% (18.07
million) [14]. Massage is generally used to relieve pain from
musculoskeletal disorders [19,20,21,22], cancer, and other condi-
tions; rehabilitate sports injuries; reduce stress; increase relaxation;
decrease feelings of anxiety and depression; and aid general

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wellness [12,21,23,24,25,26,27,28,29,30,31,32,33,34,35]. Howev-
er, only a relatively small body of research exists exploring the
efficacy of massage therapy for any condition.
In 2006, we reported results of a pilot study of massage therapy
for OA of the knee [18]. Subjects with OA of the knee meeting
American College of Rheumatology Criteria [36] were random-
ized to biweekly (4 weeks), then weekly (4 weeks) Swedish massage
(1 hour sessions) or wait list. Subjects receiving massage therapy
demonstrated significant improvements in the Western Ontario
and McMaster Universities Osteoarthritis Index (WOMAC)
[37,38,39] pain, stiffness, and physical functional disability
domains (p,0.001) and visual analog pain scale [39] (p,0.01)
[18], compared to usual care. Notably, the benefits persisted up to
8 weeks following the cessation of massage [40]. Despite these
promising results, there was no data to determine whether the dose
utilized in the pilot study was optimal.
Here, we report the results of our Phase 2 dose-finding study to
identify a dose and treatment regimen of an 8-week course of a
standardized Swedish massage therapy for OA of the knee that is
both optimal (providing greatest effectiveness) and practical
(minimizing patient cost and inconvenience). To our knowledge,
this was the first dose-finding study of massage therapy for OA,
and for OA of the knee specifically. This trial employed a more
diverse subject population at two clinical sites, and assessed longer-
term residual effects, than did our earlier pilot study. In addition, a
formally manualized massage protocol was developed and utilized
[18]. Results of the trial reported herein will inform the dosing
regimen for future clinical trials designed to confirm the efficacy of
massage therapy for osteoarthritis of the knee and define its place
in clinical practice.
Methods
The protocol for this trial and supporting CONSORT checklist are
available as supporting information; see Checklist S1 and Protocol S1.
Ethics Statement
The study protocol, consent form and all recruitment materials
were approved by the Institutional Review Boards of the
University of Medicine and Dentistry of New Jersey (Newark,
NJ), Griffin Hospital (Derby, CT), and the Saint Barnabas Medical
Center (Livingston, NJ). The study was conducted in accordance
with the Declaration of Helsinki.
Participants
Eligible patients were men and women with radiographically-
established OA of the knee who met American College of
Rheumatology criteria [36], were at least 35 years of age, and had
a pre-randomization score of 40 to 90 on the visual analog pain
scale. Patients with bilateral knee involvement had the more
severely affected knee (determined by the patient) designated as
the study knee. Subjects using NSAIDS or other medications to
control pain were included if their doses remained stable three
months prior to starting the intervention.
Subjects were excluded if they suffered from rheumatoid
arthritis, fibromyalgia, recurrent or active pseudogout, cancer, or
other serious medical conditions. Subjects were also excluded if
they had signs or history of kidney or liver failure; unstable asthma;
knee replacement of both knees; reported recent use (4 weeks–1
year prior to enrollment) of oral or intra-articular corticosteroids
or intra-articular hyaluronate; or knee arthroscopy or significant
knee injury one year prior to enrollment. A rash or open wound
over the knee and regular use of massage therapy (greater than
once a month) also resulted in exclusion from the study.
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Dose-Finding Study of Massage for Osteoarthritis
Those passing telephone screening (n = 125), agreeing to the
study protocol, and providing a written physician confirmation of
OA were scheduled for an on-site evaluation to provide written
informed consent and undergo clinical eligibility screening. All
subjects received nominal compensation (consisting of gift
certificates for future massages) for their participation. The
intervention was delivered at two sites; St. Barnabas Ambulatory
Care Center (Livingston, NJ), and the Integrative Medicine Center
at Griffin Hospital (Derby, CT). Subject participation and flow are
shown in Figure 1.
Recruitment and screening commenced in July 2009 in
Livingston, New Jersey and Southern Connecticut through flyers,
newspaper advertisements, and press releases. Information letters
were sent to patients identified with OA, as well as physicians in
the rheumatology and internal medicine practices at Saint
Barnabas Medical Center (Livingston, NJ) and Griffin Hospital
(Derby, CT). Of the 430 persons screened for eligibility, 168 did
not meet eligibility criteria, 43 refused to participate, and 94 were
not screened for other reasons (Figure 1). The most common
reasons for ineligibility were 1) no documented confirmation of
OA of the knee, 2) recent history of cortisone and hyaluronate
injections, and 3) history of knee replacement. Enrollment
continued until July 2010. 125 subjects were randomized to
receive one of four active massage arms (Groups 1–4) and one
Usual Care/control arm.
Randomization
Participants were block randomized using a permuted block
design (blocks of 5 or 10) in a 1:1:1:1:1 ratio and stratified by site
and body mass index (BMI) to ensure balance between the
intervention and Usual Care groups across the two performance
sites.. The study statistician (VYN) generated the random
allocation sequence using SAS Software version 9.1. Each eligible
and consented subject (identified by number) was assigned to one
of the treatment arms. Treatment allocation was only known by
the statistician and the study assistants (CM and AD) that assigned
participants to interventions and generated visit schedules.
Study Design and Interventions
This study was a randomized clinical trial with four treatment
arms (and one Usual Care arm) designed to assess the effects of 8
weeks of a standardized Swedish massage protocol (see Manualiza-
tion) provided at four distinct doses (Figure 1). Group 1 received
30 minutes of massage weekly for eight weeks. Group 2 received
30 minutes of massage twice weekly for the initial four weeks, and
once weekly for the remaining four weeks. Group 3 received
60 minutes of massage weekly for eight weeks. Group 4 received
60 minutes of massage twice weekly for the initial four weeks, and
once weekly for the remaining four weeks. Group 4 received the
same dosing regimen as was given in our pilot trial [41]. The
Usual Care group continued with their current treatment without
the addition of massage therapy.
The doses were chosen as practical regimens that are commonly
used in massage therapy and were designed to investigate the
variables of length of individual treatment (30 min vs. 60 min),
frequency (weekly vs. twice weekly), and total treatment time
(240 min (Group 1, 30 min weekly68 wk), 360 min (Group 2,
30 min biweekly64 wk+30 min weekly64 wk), 480 min (Group
3, 60 min weekly68 wk), or 720 min (Group 4, 60 min biweek-
ly64 wk+60 min weekly64 wk)).
Manualization
Prior to enrolling subjects, a formal manualization process
produced a study protocol that was tailored to subjects with OA of
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Figure 1. Participant Flow Diagram.
doi:10.1371/journal.pone.0030248.g001
the knee, while respectful of the individualized nature of massage
therapy [42]. The manualization process, conducted over the
course of two months, involved the input of licensed massage
therapists that participated in the pilot study, massage researchers,
as well as the investigative team. The resulting massage protocol
was made reproducible, using standard massage techniques
[18,43], as well as flexible for individual subject variability.
The manualized protocol specifies the body regions to be
addressed; with distinct 30 and 60-minute protocols (Table 1), as
well as the standard Swedish strokes to be used (effleurage,
petrissage, tapotement, vibration, friction, and skin rolling) [18].
Each protocol specifies the time allocated to various body regions
(lower/upper limbs, lower/upper back, head, neck, chest). The
protocol was specifically designed to address symptoms of
osteoarthritis of the knee. The order of body regions is not
specified in order to account for individual practitioner preference.
The manual specifies intentions/attentions for the study massage
therapists. Each study therapist was taught and agreed to the
protocol and signed a form attesting to adherence to the study
protocol after each massage session. Study personnel reviewed
adherence to the protocol at regular intervals throughout the study
period. No deviations from the manualized massage protocol
occurred.
Primary outcome measure
The primary outcome measure was change in the Western
Ontario and McMaster Universities Arthritis Index (WOMAC–
Global). The WOMAC has been used extensively in the
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Dose-Finding Study of Massage for Osteoarthritis
quantitative assessment of OA of the knee, and has been proven
to be effective in assessing pain in those suffering from the illness
[37,38,44]. It assesses dimensions of pain, functionality and joint
stiffness through 24 questions. The WOMAC has been subject to
numerous validation studies to assess reliability and responsiveness
to change in therapy, including physical forms of therapy
[37,38,44] and was successfully utilized in the Phase 1 study [18].
Secondary outcome measures
Secondary measures included pain as measured on a visual
analog scale (0 to 100 scale), a validated [39] mechanical scale
used to measure pain sensation intensity evoked by nociceptive
stimuli [45]. Other secondary outcomes were joint flexibility,
defined as the range of motion (ROM) allowed at the knee during
flexion using a double-armed goniometer, and measured time to
walk 50 feet (15 m) on a level surface within the clinic facilities.
Outcomes were assessed at baseline, 8-weeks, 16-weeks, and 24-
weeks post-baseline. Assessment visits were scheduled by a
research assistant, though the measurements were assessed by
separate personnel blinded to treatment assignments. Adherence
was assessed by tracking the number of massage visits that subjects
completed.
Statistical Analysis
Statistical analysis was conducted using SAS software (Version
9.1, SAS Institute, Cary, NC). Repeated measures ANOVA using
linear mixed model regression was used to determine between-
group changes in all outcome measures and changes in domain-
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Table 1. 30- and 60-Minute Massage Protocols.
30 minute protocol (25 minutes of table time)
Region Time Allotted
Lower Limbs 12–15 min (45–50% of session)
Upper Body 8–12 min (36–44% of session)
Discretionary 2–5 min (6–19% of session)
60 minute protocol (55 minutes of table time*)
Lower Limbs 20–27.5 min (45–50% of session)
Upper Body 15–24 min (36–44% of session)
Discretionary 3.5–20 min (6–19% of session)
*Accounting for time spent in transition including the welcome, transition to the massage room, taking off jewelry, and other preparatory activities.
doi:10.1371/journal.pone.0030248.t001
specific (i.e. pain, stiffness, and functionality) WOMAC measures,
controlling for time-dependent variables. In all analyses, a two-
tailed a of less than 0.05 was considered statistically significant.
Duncan’s multiple range test (a multiple comparison test) was used
to determine whether means differ significantly across treatment
groups. A dose-response curve was plotted assessing the magnitude
of improvement on 8-week WOMAC Global scores plotted
against the total 8-week dose of massage. A sample size of 125
individuals in five arms was based on budgetary and logistical
constraints.
Results
Of the 125 enrolled subjects, 119 completed the 8-week
assessment and 115 completed the entire trial (Figure 1). Subjects
received the intervention between November 2009 and October
2010.
Baseline characteristics of the study participants are provided in
Table 2. The randomization process with stratification by BMI
was largely successful in producing equivalent groups. The only
differences seen at baseline were that Group 1 was older than the
other groups, and Group 3 had more perceived pain than usual
care as assessed by the visual analog scale, though no differences
were seen in the pain subscale of the WOMAC.
Primary Outcome
WOMAC Global scores improved significantly (24.0 points,
95% CI ranged from 15.3–32.7) in the 60-minute massage groups
compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the
primary endpoint of 8-weeks (Table 3). No statistically significant
differences between the massage groups were detected at 8 weeks,
though the magnitude of change in the groups receiving 60-minute
doses (Groups 3 and 4) was greater than the magnitude of change
in the groups receiving 30-minute doses (Groups 1 and 2) (Table 3).
WOMAC Pain Subscale
The 60-minute doses (Groups 3 and 4) were also significantly
(27.2–27.7 points, 95% CI ranged from 18.0–36.9 points) im-
proved compared to usual care (5.6 points, 95% CI ranged from
21.9–13.1) at 8-weeks (Table 3). Significant improvement
(p,0.05) from baseline was achieved for all massage groups at 8
weeks, and at 16 and 24 weeks for the three highest doses of
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Dose-Finding Study of Massage for Osteoarthritis
Distribution
From knee down including lower leg, ankle, and foot. From knee up
including hips, pelvis, buttocks & thigh.
Lower and upper back. Head/Neck/Chest
Therapist to expand treatment to other affected areas; i.e. rib cage, flank,
upper limbs, etc.
From knee down including lower leg, ankle, and foot. From knee up
including hips, pelvis, buttocks and thigh.
Lower and upper back. Head, neck, and chest.
Therapist to expand treatment to other affected areas; i.e. rib cage, flank,
upper limbs, etc.
massage (Groups 2, 3 and 4), whereas no improvement (p.0.05)
in Usual Care was seen at any time point (Tables 3 and 4).
WOMAC Stiffness Subscale
No significant between-group changes were seen in WOMAC
Stiffness, though the magnitude of change was greater in all
treatment groups compared to usual care.
WOMAC Functionality Subscale
The 60-minute doses (Groups 3 and 4) were significantly (21.2–
22.0 points, 95% CI ranged from 12.5–31.6 points) improved
compared to usual care (6.6 points, 95% CI ranged from 0.9–12.2)
at 8-weeks (Table 3).
Dose Response
A dose-response curve based on changes in WOMAC Global
scores at 8-weeks shows increasing effect with greater total time of
massage, but with a plateau at the 480-minute dose (Group 3)
(Figure 2).
Visual Analog Pain Scale
Pain perception improved significantly (31.2–39.8 points, 95%
CI ranged from 22.9–48.1 points) in both 60-minute dose groups
(Groups 3 and 4) compared to Usual Care at 8-weeks post
baseline, with no significant differences between Groups 3 and 4.
All treatment groups reported decreased pain perception com-
pared to baseline at all time points (Tables 3 and 4).
Timed 50-foot walk
All groups showed decreased time to walk 50 feet at all time
points, except group 1 at week 8 (Tables 3 and 4). However, there
were no significant differences between the groups at any
timepoint.
Range of Motion
No significant between-group differences were seen in range of
motion at 8-weeks post-baseline, though all massage groups
changed in the positive direction. Group 4, the highest total dose
of massage, was significantly improved from baseline at all time
points. The 30-minute protocols and Usual Care groups did not
demonstrate any significant changes from baseline at any
timepoint.
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 Dose-Finding Study of Massage for Osteoarthritis

Table 2. Demographic Characteristics and Baseline Values.

Variable Group 1 (n = 25) Group 2 (n = 25) Group 3 (n = 25) Group 4 (n = 25) Usual Care (n = 25)

Gender
Female 15 (12.0%) 18 (14.4%) 19 (15.2%) 17 (13.6%) 19 (15.2%)
Male 10 (8.0%) 7 (5.6%) 6 (4.8%) 8 (6.4%) 6 (4.8%)
Race
White 23 (18.4%) 22 (17.6%) 19 (15.2%) 20 (16.0%) 22 (17.6%)
Asian 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.8%) 0 (0.0%)
White/Asian 0 (0.0%) 1 (0.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
African American 2 (1.6%) 2 (1.6%) 4 (3.2%) 4 (3.2%) 2 (1.6%)
Hispanic 0 (0.0%) 0 (0.0%) 1 (0.8%) 0 (0.0%) 0 (0.0%)
Unknown 0 (0.0%) 0 (0.0%) 1 (0.8) 0 (0.0%) 1 (0.8%)
Age (years) 69.968.6 61.969.5 62.6610.6 63.6613.0 63.6610.2
Body Mass Index (kg/m2) 31.067.5 32.166.8 31.866.7 31.367.1 31.766.5
WOMAC (mm)
Pain 52.3619.9 42.4623.0 52.5616.5 44.4619.3 46.3615.4
Stiffness 53.4624.1 58.6621.1 58.4624.7 51.2624.4 62.8618.2
Functionality 52.9617.9 49.5619.5 49.8619.7 48.3620.2 50.5617.4
Global 52.9618.3 50.2619.4 53.6617.3 48.0619.0 53.2614.8
Pain (VAS) (mm) 61.2616.8 64.0612.7 66.4611.3 59.2613.3 57.669.0
50-foot walk (seconds) 18.366.9 16.867.0 15.663.2 15.765.4 15.762.8
Range of Motion (degrees) 108.7614.6 114.4610.4 115.3610.5 112.8612.6 115.669.6

Values are mean 6 SD except otherwise stated.

doi:10.1371/journal.pone.0030248.t002

Adherence
Subjects completing 80% or more of assigned visits (8 or 12
visits, based on treatment assignment) were considered adherent;
119/125 subjects were adherent to all assigned massage visits with
no significant differences in adherence between treatment
assignments (Figure 1).
Adverse Effects
No adverse effects related to the intervention were seen during
the course of the study.
Discussion
This was the first formal dose-finding study of massage therapy
for any condition. This study investigated four different doses of
tailored Swedish massage, varying both the time (30 vs.
60 minutes per treatment) and frequency (once a week vs. twice
a week for the first month) to determine an optimal, practical dose
to use in future studies. Our manualized protocol incorporated
standard Swedish massage techniques focused on osteoarthritis of
the knee, based on the protocol used in our Phase 1 study. We
operationally defined ‘optimal-practical’ as ‘producing the greatest

Table 3. Mean change (95% CI) in outcomes at 8-weeks post-baseline (primary endpoint).

GROUP (n) Group 1 (n = 22) Group 2 (n = 24) Group 3 (n = 24) Group 4 (n = 25) Usual Care (n = 24)

DOSE 30 min 16/wk 30 min 26/wk 60 min 16/wk 60 min 26/wk (no massage)

TOTAL MASSAGE RECEIVED 240 min 360 min 480 min 720 min 0 min

WOMAC (mm)
Pain 215.1 (223.4, 26.8) 214.4 (223.8, 25.1) 227.2 (236.3, 218.0){ 227.7 (236.9, 218.6){ 25.6 (213.1, 1.9)
Stiffness 219.0 (230.4, 27.6) 223.4 (234.5, 212.3) 223.7 (234.6, 212.7) 222.3 (232.9, 211.6) 26.7 (215.7, 2.2)
Functionality 218.0 (225.5, 210.4) 217.2 (226.9, 27.6) 221.2 (229.3, 213.1){ 222.0 (231.6, 212.5){ 26.6 (212.2, 20.9)
Global 217.4 (225.3, 29.4) 218.4 (227.5, 29.2) 224.0 (232.1, 215.9){ 224.0 (232.7, 215.3){ 26.3 (212.8, 0.1)
Visual Analog Scale (mm) 214.2 (225.0, 23.4) 226.1 (236.8, 215.3) 239.8 (248.1, 231.4){{ 231.2 (239.4, 222.9){ 29.8 (218.6, 21.1)
50-foot walk (seconds) 21.3 (23.0, 0.4) 22.4 (24.7, 20.1) 21.7 (22.7, 20.6) 22.0 (23.4, 20.6) 21.3 (22.4, 20.2)
Range of Motion (degrees) 22.5 (27.5, 2.6) 24.8 (29.9, 0.4) 21.3 (26.2, 3.5) 26.6 (211.6, 21.6) 0.2 (24.1, 4.4)

Values are mean with 95% confidence intervals; negative values indicate improvement;
{
Significant (non-overlap) compared to Usual Care;
{
Significant (non-overlap) compared to Group 1.
doi:10.1371/journal.pone.0030248.t003

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 Dose-Finding Study of Massage for Osteoarthritis

Table 4. Changes in outcomes at 24-weeks post-baseline.

GROUP (n) Group 1 (n = 22) Group 2 (n = 24) Group 3 (n = 24) Group 4 (n = 25) Usual Care (n = 24)

DOSE 30 min 16/wk 30 min 26/wk 60 min 16/wk 60 min 26/wk (no massage)

WOMAC (mm)
Pain 212.2 (222.4, 22.0) 23.9 (212.7, 4.9) 213.7 (223.4, 24.0) 214.2 (224.5, 23.8) 27.5 (216.0, 1.1)
Stiffness 215.4 (226.4, 24.5) 29.6 (220.6, 1.3) 216.9 (228.5, 25.2) 216.8 (229.7, 23.9) 26.4 (213.2, 0.4)
Functionality 215.3 (224.5, 26.1) 27.4 (214.8, 0) 212.1 (222.0, 22.1) 214.4 (223.4, 25.4) 24.2 (211.1, 2.7)
Global 214.3 (222.9, 25.7) 27.0 (215.6, 1.6) 214.2 (223.4, 25.0) 215.1 (225.1, 25.1) 26.0 (212.6, 0.5)
Visual Analog Scale (mm) 214.4 (225.9, 22.8) 214.0 (224.7, 23.3) 218.5 (229.0, 28.1) 222.8 (235.5, 210.1) 211.5 (221.0, 22.0)
Time to walk 50 Feet (seconds) 22.4 (24.4, 20.4) 21.8 (23.6, 0) 21.4 (22.8, 0) 21.8 (23.3, 20.3) 21.4 (22.6, 20.2)
Range of Motion (degrees) 24.76(210.9, 1.5) 0.4 (25.7, 4.8) 22.7 (27.6, 2.3) 28.3 (214.2, 22.5) 20.3 (24.7, 4.1)

Values are mean with 95% confidence intervals; negative values indicate improvement.
doi:10.1371/journal.pone.0030248.t004

ratio of desired effect compared to costs (in time, labor, and
convenience).’ If the most effective dose were the least labor-
intensive, ‘optimal’ and ‘optimal-practical’ would be the same.
We were also interested in seeing whether the promising results
of our pilot study would be repeated and extended with this now
manualized protocol of Swedish massage, with a more diverse
population at two sites, with a longer follow up period. The
potential effectiveness of this treatment was further supported in
this study, as all massage doses demonstrated significant
improvement from baseline, as well as differences from usual care
in WOMAC Global scores at the termination of massage (8-week
timepoint). In addition, all massage groups reported significantly
decreased WOMAC Pain as assessed by VAS at the 8-week
timepoint compared to baseline, which was also different from
usual care for the three highest doses.
Angst et. al estimated minimal clinically important differences
(MCID) in WOMAC global scores (for improvement) to be 18%
change from baseline [46], while Escobar et al. found that a
MCID is approximately 15 points in patients following total knee
replacement [47]. In our study, subjects receiving the 60-minute

Figure 2. Dose-Response Curve. Dose-response curve plotting dose (total minutes over the course of 8-weeks of massage) (x-axis) vs.
improvement (change in WOMAC Global scores after 8-weeks). Dose-response effects plateaued at 480-minutes (Group 3), with no significant
improvements noted in the 720-minute (Group 4) dose.
doi:10.1371/journal.pone.0030248.g002

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doses improved a mean of 24.0 points in WOMAC global scores
(44%–50% change from baseline). Thus, the magnitude of change
in WOMAC scores is highly clinically significant.
Our results suggest a benefit of increasing massage dose with
diminishing returns at the highest level. Our dose-response curve
based on WOMAC Global scores indicates increasing improve-
ment with greater total dose (minutes) of massage, with a threshold
effect at the 480-minute dose (Group 3). While it is difficult to tease
out differences due to total dose and effectiveness of 30 vs.
60 minute individual treatments, due to the design of the study,
there is a clear trend for greater magnitude of changes in our
outcomes in both of the 60-minute doses (Groups 3 and 4),
compared to baseline, usual care, and the 30-minute dose groups.
There were no significant differences when comparing the 60-
minute groups to each other at any time point or for any outcome.
WOMAC subscales generally followed the pattern of the global
scores, with strongest responses for the higher doses.
The durability of the response in improvement of OA symptoms
and functionality to massage treatment was also supported by the
results of this study. Our Phase 1 trial [18] demonstrated
significant effects of massage therapy 16-weeks post-baseline on
the WOMAC, visual analog pain scale, and the 50-foot timed
walk. Anticipating similar effects, we assessed subjects at 16 weeks
and extended our observations to 24-weeks post-baseline.
Although the magnitude of effects was strongest after 8 weeks of
treatment and generally decreased with time, the persistence of
improvements at 2 months and 4 months after treatment cessation
indicate that the effects of the 8 weeks of massage go beyond
immediate changes to longer term shifts that may be global and/or
localized to the knee, suggesting that periodic maintenance doses
of massage may help sustain effects over time. The mechanisms for
such persistent benefit are not fully elucidated, and clearly warrant
investigation.
All massage groups demonstrated significant improvement in
WOMAC Global scores at 16 and 24 week timepoints compared
to baseline, whereas those in the usual care group did not
(Figure 3). The three highest doses of massage improved relative to
baseline in WOMAC pain at 16 and 24 weeks, in stiffness at 24
weeks, and functionality at 16 and 24 weeks.
All groups, including usual care, demonstrated decreases in the
timed 50-foot walk compared to baseline, but no clear patterns of
dose effect or significant differences between the groups. Larger
groups and perhaps a 100-foot walk may be needed to detect
between-group differences. Although almost no statistically
significant differences between the massage groups and Usual
Care were seen in the 16 and 24 week time points, the
directionality of all changes was towards improvement, and the
magnitude of changes seen was greater than changes seen in Usual
Care (Table 4). Our sample size was inadequate to determine
statistically significant between-group changes, as the goal for this
Phase 2 trial was to determine an optimal-practical dose, rather
than to determine efficacy.
Future studies should incorporate larger samples that adequate-
ly power for between group changes in longer term effects of
massage therapy. The improvements in the Usual Care arm in
some outcome measures, possibly due to Hawthorne [48] or other
nonspecific effects [49], reduced the magnitude of between-group
differences, and reaffirm the importance of control groups in this
type of study.
Massage is theorized to work through a variety of mechanisms.
Increased blood circulation to the muscles promoting gas
exchange and delivery of nutrients and removal of waste products
has long been thought to be one of the outcomes and benefits of
massage, and recent studies support this effect [50,51,52,53].
PLoS ONE | www.plosone.org
Dose-Finding Study of Massage for Osteoarthritis
There is some evidence for the promotion of a relaxation response
and shift to parasympathetic nervous system activation, with
reduced heart rate, blood pressure, biochemical, (including blood
and salivary stress hormones, endorphins, and serotonin), and
brain activation changes, associated with reduced anxiety
[40,54,55,56,57,58,59]. This may be mediated through the
activation of mechanoreceptors in the deep tissues innervated by
alpha beta fibers with subsequent central nervous system (CNS)
effects on the pituitary gland and limbic system and/or other
mechanisms [60]. The need for moderate pressure to achieve
many of the effects of massage therapy may support this
mechanism, deserves further investigation, and supports light
touch as an appropriate active control for future trials
[25,51,55,58,61,62]. A recent study comparing a single session
of Swedish massage to light touch showed significant neuroendo-
crine and immune system changes over time, with differing
patterns and degree in the massage and control intervention [59].
Other potential outcomes and mechanisms of massage therapy’s
effectiveness include decreasing muscle strain, balancing muscle
tension across the joint, positive mechanical changes in muscles,
increased joint flexibility and proprioception, increased lymphatic
circulation, immunologic and inflammatory changes, improved
sleep, and blocking pain signals [32,53,63,64,65,66,67]. Research
dedicated to exploring the mechanisms of effect is clearly
warranted.
Limitations of this trial included a small sample. Further, the
truly ‘‘optimal’’ dose might differ from any of the four studied.
Although additional doses for the massage intervention could have
been considered, the regimens that were assessed conform well to
massage regimens currently in use, are advocated by massage
therapists, and were practical to implement. Our trial was also
limited to Swedish massage techniques. This limits generalizability
to other techniques, but offers the advantage of clear standard-
ization of the intervention. Swedish technique predominates in
clinical settings [68] and is thus the logical, initial choice; other
massage techniques should be compared to Swedish massage once
its efficacy is established. Further, the Swedish technique has been
successfully applied and demonstrated promise in our pilot study
[18].
As the mechanism(s) of action of massage are not fully
elucidated, it is premature to predict dose-responses for higher
or lower doses than the doses utilized in this trial, or applied to
clinical models besides osteoarthritis of the knee. For example, if
massage enhances regional blood flow, it might be that a follow-up
massage too soon (i.e. within one week) actually attenuates benefit
by applying pressure to slightly engorged tissue. Thus, there might
be an optimal periodicity to massage, with suboptimal effects seen
with dosing outside this purported ideal. Changes in neuroendo-
crine and inflammatory status, pain generation and sensitivity, or
musculature strain or balance, may also reach an optimal state,
which persists for some time, and is not enhanced by further
massage within a weeks’ time. Our study, however, did not
attempt to establish a dose-response gradient. Rather, the goal was
to establish an optimal-practical dose for future testing, based on
the combination of convenience, practicability, and therapeutic
effectiveness.
Conclusion
This dose-finding trial established an optimal dose of 60-
minutes of this manualized Swedish massage therapy treatment
delivered once weekly in an eight week protocol for OA of the
knee. This decision was based on the superiority of the 60 minute
compared to 30 minute treatments, the essentially equivalent
outcomes of the two 60 minute doses, the convenience of a once-
7 February 2012 | Volume 7 | Issue 2 | e30248

Figure 3. Improvement in WOMAC-Global Scores at Assigned Doses of Massage.
doi:10.1371/journal.pone.0030248.g003
weekly protocol (compared to biweekly), cost savings, and
consistency with a typical real-world massage protocol. As there
is promising [18], but not definite [69], potential for the utility of
massage therapy for knee osteoarthritis, future research on this
standardized approach to massage therapy should utilize this dose.
In addition, future, more definitive research is needed investigating
not only the efficacy, but also cost-effectiveness of massage for OA
of the knee and other joints, as well as research exploring the
mechanism(s) by which massage may exert its effects in this clinical
application and in general.
Supporting Information
Checklist S1 CONSORT Checklist.
(DOC)
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Acknowledgments
We thank the study subjects for their participation. Licensed massage
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